Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia

José M. Eltit, Xudong Ding, Isaac N Pessah, Paul D. Allen, José R. Lopez

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Malignant hyperthermia (MH) susceptibility has been attributed to a leaky sarcoplasmic reticulum (SR) caused by missense mutations in RYR1 or CACNA1S, and the MH crisis has been attributed solely to massive self-sustaining release of Ca2+ from SR stores elicited by triggering agents. Here, we show in muscle cells from MH-RyR1R163C knock-in mice that increased passive SR Ca2+ leak causes an enlarged basal influx of sarcolemmal Ca 2+ that results in chronically elevated myoplasmic free Ca 2+ concentration ([Ca2+]i) at rest. We discovered that Gd+3 and GsMTx-4 were more effective than BTP2 or expression of the dominant-negative Orai1E190Q in reducing both Ca2+ entry and [Ca2+]i, implicating a non-STIM1/ Orai1 SOCE pathway in resetting resting [Ca2+] i. Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and [Na]i is chronically elevated in MH-RyR1 R163C muscle cells. [Ca2+]i and [Na +]i are persistently elevated in vivo and further increased by halothane in MH-RyR1R163C/WT muscle. These increases are markedly attenuated by local perfusion of Gd+3 or GsMTx-4 and completely suppressed by dantrolene. These results contribute a new paradigm for understanding MH pathophysiology by demonstrating that nonselective sarcolemmal cation channel activity plays a critical role in causing myoplasmic Ca 2+ and Na+ overload both at rest and during the MH crisis.

Original languageEnglish (US)
Pages (from-to)991-1000
Number of pages10
JournalFASEB Journal
Volume27
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Malignant Hyperthermia
Muscle
Cations
Cells
Sarcoplasmic Reticulum
Dantrolene
Ryanodine Receptor Calcium Release Channel
Halothane
Muscle Cells
Missense Mutation
Perfusion
Grammostola spatulata MTx4 protein
Muscles

Keywords

  • Dantrolene
  • Skeletal muscle

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia. / Eltit, José M.; Ding, Xudong; Pessah, Isaac N; Allen, Paul D.; Lopez, José R.

In: FASEB Journal, Vol. 27, No. 3, 03.2013, p. 991-1000.

Research output: Contribution to journalArticle

Eltit, José M. ; Ding, Xudong ; Pessah, Isaac N ; Allen, Paul D. ; Lopez, José R. / Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia. In: FASEB Journal. 2013 ; Vol. 27, No. 3. pp. 991-1000.
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AB - Malignant hyperthermia (MH) susceptibility has been attributed to a leaky sarcoplasmic reticulum (SR) caused by missense mutations in RYR1 or CACNA1S, and the MH crisis has been attributed solely to massive self-sustaining release of Ca2+ from SR stores elicited by triggering agents. Here, we show in muscle cells from MH-RyR1R163C knock-in mice that increased passive SR Ca2+ leak causes an enlarged basal influx of sarcolemmal Ca 2+ that results in chronically elevated myoplasmic free Ca 2+ concentration ([Ca2+]i) at rest. We discovered that Gd+3 and GsMTx-4 were more effective than BTP2 or expression of the dominant-negative Orai1E190Q in reducing both Ca2+ entry and [Ca2+]i, implicating a non-STIM1/ Orai1 SOCE pathway in resetting resting [Ca2+] i. Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and [Na]i is chronically elevated in MH-RyR1 R163C muscle cells. [Ca2+]i and [Na +]i are persistently elevated in vivo and further increased by halothane in MH-RyR1R163C/WT muscle. These increases are markedly attenuated by local perfusion of Gd+3 or GsMTx-4 and completely suppressed by dantrolene. These results contribute a new paradigm for understanding MH pathophysiology by demonstrating that nonselective sarcolemmal cation channel activity plays a critical role in causing myoplasmic Ca 2+ and Na+ overload both at rest and during the MH crisis.

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